The goal of this project is elucidation of the molecular mechanisms of demyelination in the CNS, especially in viral diseases, and in demyelination diseases of unknown etiology such as multiple sclerosis. Two approaches have been utilized: (1) Role of immunity to herpes simplex virus (HSV) infection of the CNS: A model was developed in which immunization of C57BL/6 mice intraperitoneally with HSV-1 or HSV-2 allowed study of the influence of immunity on subsequent CNS demyelination following intracerebral challenge with the virus. Unfortunately, a switch in the supplier of the mice was necessitated by infection in his colony, and the new C57BL/6 mice behave differently . The problems presented have not yet been overcome, and that aspect of this project has been temporarily suspended. (2) Structure of myelin basic protein (MBP): The structure of this essential myelin component has been predicted from its known amino acid sequence. The model has an Alpha/Beta molecular organization, with two Alpha-helices between the five strands of an antiparallel Beta-sheet. The Beta-sheet faces may be loci of interaction with phospolipids on the cytoplasmic surface of the myelin membrane. This new model of a protein, previously thought to be largely disordered, is one of the most detailed protein structure predictions ever attempted. It leads directly to testable new predictions, as would be expected of a detailed model. Unexpectedly, it also leads to an entirely new biochemical mechanism for virally-induced demyelination. A key threonine phosphorylation site in MBP, which precedes the triproline sequence, is closely mimicked by certain viral proteins, including the large T antigen of the human papova virus, JC virus. JC causes the devastating demyelinating disease of immunocompromised patients known as progressive multifocal leukoencephalopathy (PML). Phosphorylation of the Thr residue, which the model indicates would be a key step in MBP processing, could be competitively inhibited by the presence of the viral protein. Whether a similar mechanism is in any way involved in the etiology of demyelination in MS is not yet known.